A new classification with respect to the serotonin (5-HT)-receptor subtype was suggested by B. P. Richardson et al as described in Nature, vol. 316, pp. 126 (1985), and the 5-HT M-receptor, which was proposed by Gaddum and Picarelli in 1957, was identified as a 5-HT.sub.3 receptor.
It has been known that the 5-HT.sub.3 receptor exists in the sensory nervous system, autonomic nervous terminal and so on, and it was also confirmed it was distributed in the central nervous system.
As the distribution of the 5-HT.sub.3 receptor becomes clear, it is suggested that the clinical applicability of blocking agents against the 5-HT.sub.3 receptor widely ranges from the peripheral system to the nervous system.
Metoclopramide is known to exhibit dopamine receptor antagonistic activity as well as 5-HT.sub.3 receptor antagonistic activity and has been used in preventing vomiting or nausea induced by anticancer agents such as cisplatin, but its antiemetic effect is not satisfactory. Further, metoclopramide induces diarrhea and the adverse reaction in the central nervous system such as extrapyramidal disturbances or sedation.
According to various studies on the relationship of the 5-HT.sub.3 receptor and vomiting, it is reported that a 5-HT.sub.3 receptor antagonist is effective but a dopamine receptor antagonist is not effective against anticancer agent-induced vomiting.
The Lancet, June 27, 1987, pp, 1470 reports that the 5-HT.sub.3 receptor antagonistic 8-methyl-8-azabicyclo[3.2.1]oct-3-yl indole-3-carboxylate (ICS 205-930) and 1,2,3,9-tetrahydro-9methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbaz ol-4-one hydrochloride (GR38032F) are effective against vomiting induced by chemotherapy, but show adverse effects such as headache, sedation, dryness of the mouth or diarrhea.
Therefore, it has been desired to develop 5-HT.sub.3 receptor antagonistic antiemetics without side effects.
DE 2509155 A specification discloses a group of 1,4-benzoxazine compounds having antiarrhythmic activity.
The present inventors noticed that the 5-HT.sub.3 receptor antagonists have various pharmacological activities such as antiemetic activity as well as potentiating activity of gastroenteromotility, analgesic activity and antiaxietic activity and made intensive investigations to develop a new and potent 5-HT.sub.3 receptor antagonist without or with less and adverse effects; as a result, the inventors have found that a new series of benzoxazine compounds show an enhanced 5-HT.sub.3 receptor antagonistic activity and completed the present invention.